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Once upon a time excipients…

Once upon a time excipients…. Penny North-Lewis Paediatric Liver Pharmacist St James's University Hospital Leeds Teaching Hospitals Trust. Dr Catherine Tuleu Senior Lecturer, Department of Pharmaceutics & Deputy Director, Centre for Paediatric Pharmacy Research.

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Once upon a time excipients…

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  1. Once upon a time excipients… Penny North-Lewis Paediatric Liver Pharmacist St James's University Hospital Leeds Teaching Hospitals Trust Dr Catherine Tuleu Senior Lecturer, Department of Pharmaceutics & Deputy Director, Centre for Paediatric Pharmacy Research

  2. CPPRCentre for Paediatric Pharmacy Research Dir: Prof IK Wong Parents Carers Formulation Medicines Child Safety Prescribers PK/PD PG Drug utilisation Compliance Adherence Concordance Pharmaco-epidemiology Spin out company: Therakind www.pharmacy.ac.uk/cppr.html

  3. Why excipients? Active Pharmaceutical Excipients Ingredients Medicine Patient Bioavailability, Therapeutic Effect, Acceptability Process Routes Administration Efficacy Safety Quality

  4. The ideal paediatric formulation: holy grail? • Paediatric single dose or • safe and convenient withdrawal of paediatric single dose • Age appropriate • Minimal dose frequency • ‘Non toxic’ excipients • Good organoleptic characteristics • Reliable safe and easy administration • Good acceptability by children and parents/carers • Optimised R&D (production vs cost) • Developing countries

  5. The main formulation challenge • EUROPEAN MEDICINES AGENCY (EMEA): ICH Topic E 11. Clinical Investigations of Medicinal Products in the Paediatric Population,EMEA/CHMP/ICH/2711/99 (2000). • COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP): Reflection paper: formulations of choice for the paediatric population. EMEA/CHMP/PEG/194810/2005 (2005).

  6. Oral Liquids: Gold standard? • Buffering agents • Solvents/Co-solvents (e.g. Ethanol, Propylene Glycol, Glycerol) • for suspensions: Suspending agents, Wetting Agents • Preservatives (e.g. Parabens, Benzoic Acid) • Antioxidants (e.g. EDTA) • Bulk (nutritive) Sweeteners (e.g. Sucrose, SF: Sorbitol, Maltitol, Mannitol,Xylitol) • Intense (non nutritive) sweeteners (e.g. Acesulfame K, Aspartam, Sucralose, Saccharin) • Flavours (natural, artificial) • Colours (natural, artificial) • Cyclodextrins, Ion exchange resins • Lipids, surfactants etc

  7. Short case • 4 week old baby with prolonged jaundice is prescribed phenobarbital 5mg/kg nocte for 5 days before a HIDA scan at a liver unit. This was dispensed by the DGH pharmacy. • Mum returns with the medicine the next day saying that she felt like her child was choking and stopped breathing when she gave the medicine and she is very worried about having to give another dose. • Why might this have happened? • What could you do instead?

  8. Ethanol Phenobarbital elixir BP 15mg/5ml contains 38% alcohol BEC (mg/100ml) = volume x % ethanol (v/v) x 0.79 0.6L/kg x weight (kg) > 80mg/100ml = drink drive limit!! Immature metabolism Higher BBB permeability Acute intoxication Interaction with other drugs, Long term (hepatorenal) consequences?

  9. Toxic Additives in Medications for Preterm Infants . Whittaker et al. Arch Dis Child Fetal Neonatal Ed. 2009 Jan 21

  10. Propylene Glycol

  11. ADI ADI <25mg/Kg BW http://jecfa.ilsi.org/search.cfm

  12. Agenerase Oral Solution Agenerase Oral Solution

  13. Toxic Additives in Medications for Preterm Infants Whittaker et al. Arch Dis Child Fetal Neonatal Ed. 2009 Jan 21

  14. Diethylene glycol instead of Propylene Glycol… Acute Toxicitiy!

  15. Balbani AP, Stelzer LB, Montovani JC. Pharmaceutical excipients and the information on drug labels.Braz J Otorhinolaryngol.2006; 72(3):400-406.

  16. AZO DYE E110 sunset Balbani AP, Stelzer LB, Montovani JC. Pharmaceutical excipients and the information on drug labels.Braz J Otorhinolaryngol.2006; 72(3):400-406.

  17. Quinoline yellow E104 Carmoisine E122 Allura red E129 Tartrazine E102 Ponceau 4R Sunset yellow E110 bronchoconstriction food allergies link between this additive and hyperactive behavioural disorders in children. McCann et al. 2007. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet Refuted by EFSA Whilst being a commonly used colour in the UK, its use is banned in Norway and Finland…

  18. Benzyl alcohol • Often antimicrobial preservative in parenterals • Fatal toxic syndrome in pre term neonates (immature metabolism) May increase risk of jaundice in neonates (displace bilirubine) • (benzoic acid, Na+ and K+ Benzoate) • Pain at injection ADI <5mg/kg BW

  19. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates Shehab et al. Pediatr Crit Care Med.2009; 10:256-259.

  20. Excipients Substances, other than the active ingredient, which have been appropriately evaluated for safety WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 885 - Thirty-fifth Report (1999)

  21. Sorbitol etc Sucrose Or SF....?

  22. Excipients with elevated toxicological risks Breitkreutz & Boos 2007 Expert Opinion on Drug Delivery 4(1):37-45

  23. Excipients with elevated toxicological risks

  24. Risk-benefit assessment • Safety Profile of Excipient • Quantity • Exposure • Route of administration (ADME) • Patient (age, disease) • Manufacturability • ‘Black list’ • Solubilizing agents • Preservatives • Bulk Sweeteners • Intense Sweeteners • Flavouring, Colouring agents • etc • Excipients in Liquid Medicines! And what about… residual solvents Impurities Desorption from tubes and packaging materials

  25. And now, case scenarios

  26. About the licensing system… Adapted from Cuzzolin et al. 2006. Expert Opin. Drug. Saf. 5:703-718 ~40% of Off Label or Unlicensed drug prescribed are involved in an Adverse Drug Reaction Medication Errors are 3 times more common in children than in adults Kaushal et al. JAMA (2001)

  27. The EU paediatric regulation • Since January 2007 • 3 pilars: • Obligation : Paediatric Investigation Plan (PIP) • Paediatric Committee (PDCO) at the EMEA • Reward (incentives) for studies conducted • results are included in the product information (SPC) = medicine eligible forsix months’ patent extension • even if clinical trial do not show efficacy

  28. The future is bright(er) PIP • Overall strategy • Review any information on the product such as: • Suitability of the existing pharmaceutical form (tablets vs liquid, new strength…) • Off label or unlicensed use • Strategy in relation to quality aspect • Address Critical issue such as: • The need for a specific formulation or dosage form in relation to age group – discussion of the benefit • Availability/timeframe for the development • Potential issues (e.g. excipients) • Administration (use of specific device, ability to mix with food, socio-cultural issues, packaging)

  29. www.emea.europa.eu/pdfs/human/qwp/13893108en.pdf • Guideline being prepared by Quality Working Party drafting group– consultation expected soon

  30. ERANET PRIOMEDCHILD To support researchers working together internationally allowing them to address important research questions that they could not address otherwise - The development or use of innovative methodology in medicines for children research - Innovation of paediatric formulations and drug delivery systems The studies on novel modes of drug delivery (buccal, nasal, transdermal), age specific formulations, Innovation on taste masking and improved dosing devices Risk assessment and data collection on excipients. 8.5 -10 million Euros www.priomedchild.eu/index.php?id=6574

  31. Data base on Excipients for paediatric medicines EuPFi and PFI (US) are building a database which will be available freely on a website Thanks for your attention And now, the Sunday morning QUIZ!!!

  32. Question 1 – The ideal paediatric formulation should have all of the following characteristics EXCEPT: • A A full range of dosage formulations • B Non-toxic excipients • C A minimal dosage frequency • D Not easily reproduced Paediatric Formulations – Pharmaceutical Excipients and Adverse ReactionsThis MCQs have been prepared from the PEP (Pharmacist Education programme) developed by IDIS

  33. Question 2 – What is the recommended target dose volume for children under the age of 5 years? • A 2.5 ml or less • B 5 ml or less • C 7.5 ml or less • D 10 ml or less

  34. Question 3 – Effervescent tablets are unsuitable for which of the following patient groups? • A Children with renal impairment • B Epileptic patients/children calcium restricted • C Infants • D Adolescents

  35. Question 4 – Which of the following excipients can cause jaundice in neonates? • A Benzoic acid • B Aspartame • C Lactose • D Propylene glycol

  36. Question 5 – Which of the following excipients should be avoided in children under three years old due to the risk of Central Nervous System (CNS) depression? • A Benzyl alcohol • B Aspartame • C Lactose • D Propylene glycol

  37. Question 6 – Which of the following excipients is associated with hyperactive behaviour? • A Sucrose • B Sorbitol • C Azodyes • D Fructose

  38. Question 7 – The use of which of the following orally toxic excipients was linked to death when used as a solvent? • A Lactose • B Aspartame • C Propylene glycol • D Diethylene glycol

  39. Question 78 – Which of the following is used as a solvent and preservative? • A Benzyl alcohol • B Arachis oil • C Propylene glycol • D Diethylene glycol

  40. Question 9 – Which of the following excipients is NOT used as a solvent? • A Propylene glycol • B Benzyl alcohol • C Ethanol • D Arachis oil

  41. Question 10 – Which of the following is a source of phenylalanine? • A Saccharin • B Aspartame • C Sorbitol • D Fructose

  42. Question 11 – Which of the following sweeteners should be avoided in patients with a sulphonamide allergy? • A Saccharin • B Aspartame • C Sorbitol • D Fructose

  43. Question 12 – Which of the following preservatives is associated with a potentially fatal toxic syndrome in neonates? • A Benzyl alcohol • B Sodium benzoate • C Benzoic acid • D Propylene glycol

  44. Question 13 – Which of the following preservatives is NOT associated with jaundice in neonates? • A Thiomersal • B Sodium benzoate • C Benzoic acid • D Potassium benzoate

  45. Question 14 – In neonates the daily benzyl alcohol dose should be limited to: • A 5mg/kg or less • B 10mg/kg or less • C 15mg/kg or less • D 20mg/kg or less

  46. Question 15 – In the event that a repeat prescription for a paediatric medicine is presented to the pharmacy for a child with severe allergy to a pharmaceutical excipient, the most appropriate course of action would be: • A Confirm with the carer which product was used previously • B Check the Summary of Product Characteristics (SPC) for details on excipients • C Check the BNFc for details on excipients • D Contact the manufacturer for details on excipients

  47. Question 16 – What average percentage of medicines used by children in Europe are untested or unauthorised for paediatric use, according to the European Medicines Agency (EMEA)? • A At least 5% • B At least 10% • C At least 25% • D At least 50%

  48. Question 17 – The European regulations on medicinal products for children came into force in which year? • A 2005 • B 2006 • C 2007 • D 2008

  49. Question 18 – According to the International Conference on Harmonisation, the term ‘child’ applies to which age range? • A Birth to one month • B One month to two years • C Two to 12 years • D 12 to 18 years

  50. Question 19 - Under the new European Regulation, studying medicines for use in children will be rewarded by • A Funding incentives • B Patent extension of 6 months • C Patent extension for 12 months • D Patent extension for 18 months

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